Restoration of β cell mass via β cell regeneration is a promising approach for treatment of diabetes. However, β cell proliferative capacity declines after adolescence and remains extremely low during entire adulthood, posing a significant roadblock in β cell regeneration therapy. The mechanism that inhibits β cell replication in adult and obesity remains enigma. Toll-Like Receptors (TLRs) are membrane-spanning proteins that recognize microbes-derived structurally conserved molecules and play a key role in innate immune response. Serendipitously, our study demonstrated that Toll-like receptor (TLR) 2/TLR4 act as molecular “brakes” for diet-induced β cell replication in both mice and humans. The combined loss of TLR2/TLR4, but not individually, dramatically increases facultative β, not α, cell replication, leading to progressively enlarged β cell mass and hyperinsulinemia in diet-induced obesity. Mechanistically, loss of TLR2/TLR4 increases β cell proliferation and nuclear abundance of Cyclin D2 and cyclin-dependent kinase 4 (CDK4) in an extracellular signal-regulated kinase (ERK)-dependent manner. These data reveal a novel negative regulatory mechanism governing adaptive β cell mass expansion in diet-induced obesity and suggest that selective targeting of TLR2/TLR4 pathways may hold promise for reversing β cell failure in diabetic patients.
Y. Ji: None. S. Sun: None. L. Qi: None.
American Diabetes Association (1-12-CD-04, 1-19-IBS-235 to L.Q.); JDRF (47-2012-767, 1-SRA-2014-251-Q-R, 2-SRA-2018-539-A-B); American Heart Association (17SDG33670192); Michigan Nutrition Obesity Research Center (P30DK089503); Howard Hughes Medical Institute (59107338)